Durvalumab Alone or in Combination with Tremelimumab and Chemotherapy versus Chemotherapy Alone as First-Line Treatment for Metastatic NSCLC: POSEIDON Study

The treatment for advanced non–small-cell lung cancer (NSCLC) has improved greatly over the past years. PD-1/PD-L1 inhibitors as monotherapy and combined with chemotherapy have both been instrumental in this; however, there is still a need for better therapy.

The POSEIDON trial is an international, multicenter phase 3 study of first-line treatment of patients with NSCLC whose tumors do not have EGFR mutations or ALK fusions (N = 1013). Patients in this trial were treated with durvalumab (DURV) plus tremelimumab (TREM) plus standard-of-care (SOC) chemotherapy, DURV monotherapy plus SOC chemotherapy, or SOC chemotherapy alone.^1-3 Patients were randomized 1:1:1 to receive either DURV 1500 mg every 4 weeks plus chemotherapy every 3 weeks for 4 cycles and then maintenance DURV 1500 mg every 4 weeks plus pemetrexed, or DURV 1500 mg plus TREM 75 mg plus chemotherapy every 3 weeks for 4 cycles and then maintenance DURV 1500 mg every 4 weeks plus TREM 75 mg at week 16 and pemetrexed, or platinum-based chemotherapy every 3 weeks for up to 6 cycles, then maintenance pemetrexed. SOC chemotherapy consisted of abraxane plus carboplatin for NSCLC with squamous and nonsquamous histologies, gemcitabine plus cisplatin or carboplatin for squamous patients only, and pemetrexed plus cisplatin or carboplatin for nonsquamous patients only. The therapies were each continued until disease progression.^1-3 The patients were stratified by PD-L1 expression, disease stage, and histology.²

The primary end points were progression-free survival (PFS) and overall survival (OS) for DURV plus chemotherapy compared with chemotherapy alone. The secondary end points were PFS and OS for DURV plus TREM plus chemotherapy compared with chemotherapy alone.^1-3 The objective response rate (ORR), duration of response (DOR), best objective response, and 1-year PFS were additional outcome measures investigated, in addition to safety, tolerability, and health-related quality of life.^2,3

The median PFS for DURV plus chemotherapy was 5.5 months (95% confidence interval [CI], 4.7-6.5) compared with 4.8 months for chemotherapy alone (95% CI, 4.6-5.8) and 6.2 months for DURV plus TREM plus chemotherapy (95% CI, 5.0-6.5).

The 1-year PFS rates were 24.4% (95% CI, 19.7-29.5) for DURV plus chemotherapy compared with 13.1% (95% CI, 9.3-17.6) for chemotherapy alone, and 26.6% (95% CI, 21.7-31.7) for DURV plus TREM plus chemotherapy.^2,3

The median OS was 13.3 months (95% CI, 11.4-11.7) for DURV plus chemotherapy and 11.7 months (95% CI, 10.5-13.1) with chemotherapy alone (hazard ratio [HR], 0.86; 95% CI, 0.72-1.02; P = .07581 [not statistically significant]).³ However, for DURV plus TREM plus chemotherapy, median OS was 14.0 months (95% CI, 11.7-16.1) compared with 11.7 months for chemotherapy alone (HR, 0.77; 95% CI, 0.65-0.92; P = .00304).³

The 2-year OS rates were 29.6% (95% CI, 24.8-34.6) for DURV plus chemotherapy, 22.1% (95% CI, 17.8-26.8) for chemotherapy alone, and 32.9% (95% CI, 27.9-37.9) for DURV plus TREM plus chemotherapy.^2,3

ORRs were 41.5% for DURV plus chemotherapy, 38.8% for DURV plus TREM plus chemotherapy, and 24.4% for chemotherapy alone.³ The DOR was 7.0 months (95% CI, 5.7-9.9) for DURV plus chemotherapy, 9.5 months (95% CI, 7.2-not estimable) for DURV plus TREM plus chemotherapy, and 5.1 months (95% CI, 4.4-6.0) for chemotherapy alone.³ This response was maintained at 12 months in 38.9% of the DURV plus chemotherapy group, 49.7% of the DURV plus TREM plus chemotherapy group, and 21.4% of the chemotherapy-alone group.³

All-grade, all-cause adverse events (AEs) occurred in 96.1% of the DURV plus chemotherapy group (54.8% grade 3/4), 97.3% of the DURV plus TREM plus chemotherapy group (53.3% grade 3/4), and 96.1% of the chemotherapy-alone group (51.7% grade 3/4). Serious AEs occurred in 40.1%, 44.2%, and 35.1% of the DURV plus chemotherapy group, DURV plus TREM plus chemotherapy group, and chemotherapy-alone group, respectively.³

Treatment-related AEs (TRAEs) occurred in 88.6% of patients treated with DURV plus chemotherapy, 92.7% of patients on DURV plus TREM plus chemotherapy, and 89.5% of patients on chemotherapy alone.³ Of the TRAEs, 44.6%, 51.8%, and 44.4% were grade 3/4 in the DURV plus chemotherapy, DURV plus TREM plus chemotherapy, and chemotherapy-alone groups, respectively.^2,3

Serious TRAEs occurred in 19.5%, 27.6%, and 17.7% of patients administered DURV plus chemotherapy, DURV plus TREM plus chemotherapy, and chemotherapy alone, respectively.³ Treatment was stopped because of TRAEs in 14.1% of patients on DURV plus chemotherapy, 15.5% on DURV plus TREM plus chemotherapy, and 9.9% on chemotherapy alone,² with death reported from TRAEs in 2.1%, 3.3%, and 2.4% of patients in those groups, respectively.³

The researchers concluded that both DURV plus chemotherapy with TREM and without TREM showed improvement in PFS when compared with chemotherapy alone for treatment of metastatic NSCLC.^2,3 In addition, DURV with TREM plus chemotherapy led to a statistically significant increase in OS compared with chemotherapy alone.² They also proposed that DURV plus TREM plus chemotherapy may be a new first-line therapy for NSCLC.²

References

1. ClinicalTrials.gov. A phase III, randomized, multi-center, open-label, comparative global study to determine the efficacy of durvalumab or durvalumab and tremelimumab in combination with platinum-based chemotherapy for first-line treatment in patients with metastatic non small-cell lung cancer (NSCLC) (POSEIDON). ClinicalTrials.gov identifier NCT03164616. Updated October 29, 2021. https://clinicaltrials.gov/ct2/show/NCT03164616. Accessed November 6, 2021.
2. Johnson ML, Cho BC, Luft A, et al. Durvalumab ± tremelimumab + chemotherapy as first-line treatment for mNSCLC: results from the phase 3 POSEIDON study. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer Virtual; September 8-14, 2021. Abstract PL02.01.
3. Mauro G. Durvalumab combo, with or without tremelimumab, improves PFS in NSCLC. Target Oncol. 2021;21:74.